Pancreatic cancer (PDAC) is a lethal disease with 5-year survival of 4% and current therapeutic options are few and ineffective. Therefore, there remains a dire need for novel targeted therapies for this cancer. Recent studies have implicated the importance of signaling pathways that activate the Rac small GTPase in PDAC tumorigenic growth and invasion. We therefore hypothesize that inhibitors of Rac signaling will be an effective strategy for PDAC treatment. However, while well validated as key disease drivers, Rac and other small GTPases (e.g. Ras) are not currently considered to be attractive or druggable targets for cancer treatment. While recent synthetic lethality genetic screens have been established to identify key components of Ras oncogenesis, no such mammalian cell assay has been identified for Rac. Therefore, novel approaches are needed. We have established, validated and performed a novel C. elegans-based positive-selection functional screen for (a) identifying genes whose functions are critical for Rac activity and (b) high-throughput chemical library screening to identify small molecule inhibitors of Rac lethality. In our model, constitutive activation of the Rac ortholog in C. elegans, CED-10, causes 100% lethality, thus providing positive selection for our genetic and pharmacologic screens. This model combines genetic amenability, low cost and culture conditions compatible with genome wide genetic and high-throughput chemical screening in a whole animal context. Our application of this C. elegans model, when coupled with mammalian cell culture and mouse models for validation and further analyses, may identify novel approaches for blocking Rac in PDAC. If successful, our proof-of-concept studies will show that C. elegans-based models can be effective for drug discovery and will stimulate renewed interest both in targeting small GTPases and in development of other organism-based functional screens for drug discovery. We propose three aims to accomplish this goal: (1) identify the genes whose disruption specifically suppressed activated CED-10/Rac, (2) identify small molecule inhibitors that suppress CED-10/Rac lethality, and (3) apply cell- and mouse-based validation of genetically defined Rac signaling components and small molecule inhibitors. Relevance: Effective therapeutic options for pancreatic cancer, a lethal disease with 5-year survival of 4%, are few and ineffective. Traditional drug discovery approaches have not been effective in addressing this problem. We propose our application of an innovative new model system for drug discovery focused on a validated new therapeutic target for this deadly disease PUBLIC HEALTH RELEVANCE: Effective chemotherapeutic options for pancreatic cancer, a lethal disease with 5-year survival of 4%, are few and ineffective. Traditional drug discovery approaches have not been effective in addressing this problem. We propose the study of a novel target, the Rac small GTPase, and the application of a C. elegans nematode model for genome-wide genetic and high-throughput chemical screens to identify novel Rac-specific targets and therapies for pancreatic cancer.